Broad spectrum caspase inhibitors have been found to reduce neurodegeneration caused by cerebral ischemia. We studied whether blockade of group I caspases, mainly caspase-1, using the inhibitor Ac-YVAD.cmk reduced infarct volume and produced prolonged neuroprotection. Ac-YVAD.cmk (300 ng/rat) was injected intracerebroventricularly 10 min after permanent middle cerebral artery occlusion in the rat. Drug treatment induced a significant reduction of infarct volume not only 24 hr after ischemia (total damage, percentage of hemisphere volume: Control, 41.1 ± 2.3%; treated, 26.5 ± 2.1%; p <0.05) but also 6 d later (total damage: Control, 30.6 ± 2.2%; treated, 23.0 ± 2.2%; p <0.05). Ac-YVAD.cmk treatment resulted in a reduction not only of caspase-1 (control, 100 ± 20.3%; treated, 3.4 ± 10.4%; p <0.01) but also of caspase-3 (control, 100 ± 30.3%; treated, 13.2 ± 9.5%; p <0.05) activity at 24 hr and led to a parallel decrease of apoptosis as measured by nucleosome quantitation (control, 100 ± 11.8%; treated, 47 ± 5.9%; p <0.05). Six days after treatment no differences in these parameters could be detected between control and treated animals. Likewise, brain levels of the proinflammatory cytokines IL-1β and TNF-α were reduced at 24 hr (39.5 ± 23.7 and 51.9 ± 10.3% of control, respectively) but not at 6 d. Other cytokines, IL-10, MCP-1, MIP-2, and the gaseous mediator nitric oxide, were not modified by the treatment. These findings indicate that blockade of caspase-1-like activity induces a long- lasting neuroprotective effect that, in our experimental conditions, takes place in the early stages of damage progression. Finally, this effect is achieved by interfering with both apoptotic and inflammatory mechanisms.
|Number of pages||7|
|Journal||Journal of Neuroscience|
|Publication status||Published - Jun 15 2000|
- Ac- YVAD.cmk
- Caspase inhibition
- Permanent focal cerebral ischemia
ASJC Scopus subject areas